The present invention relates to compounds and pharmaceutical formulations that can be used to treat conditions mediated by nuclear hormone receptors, more specifically, to compounds and pharmaceutical formulations that modulate PPAR activity.
Hypercholesterolemia, hyperlipidemia, and diabetes are well recognized risk factors in the onset of atherosclerosis and coronary heart disease. Hypercholesterolemia and hyperlipidemia are characterized by excessively high levels of blood cholesterol and lipids. The blood cholesterol pool is generally dependent on dietary uptake of cholesterol from the intestine and biosynthesis of cholesterol throughout the body, especially the liver. The majority of cholesterol in plasma is carried on apolipoprotein B-containing lipoproteins, such as low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL). The risk of coronary artery disease in man increases when LDL and VLDL levels increase. Conversely, high levels of cholesterol carried in high-density lipoproteins (HDL) is protective against coronary artery disease (Am. J. Med., 1977; 62:707-714).
The statins represent perhaps the most important class of lipid-lowering drugs. These compounds inhibit HMG-CoA reductase which is implicated in the rate-limiting step in cellular cholesterol biosynthesis. Representative statins include atorvastatin, lovastatin, pravastatin, and simvastatin. The effectiveness of these compounds depends on LDL receptor regulation. Other important antilipidemia drugs include fibrates such as gemfibril and clofibrate, bile acid sequestrants such as cholestyramine and colestipol, probucol, and nicotinic acid analogs.
To date, a number of oral antidiabetic agents have been developed. The most commonly used hypoglygemic drugs are the sulfonylureas. Sulfonylureas are generally used to stimulate insulin. The biguanide metformin is generally used to improve insulin sensitivity and to decrease hepatic glucose output. Acarbose is used to limit postprandial hyperglycemia. Thiazolidine 2,4 diones are used to enhance insulin action without increasing insulin secretion.
Peroxisome Proliferator Activation Receptors (PPAR) are implicated in a number of biological processes and disease states including hypercholesterolemia, hyperlipidemia, and diabetes. PPARs are members of the nuclear receptor superfamily of transcription factors that includes steroid, thyroid, and vitamin D receptors. They play a role in controlling expression of proteins that regulate lipid metabolism. Furthermore, the PPARs are activated by fatty acids and fatty acid metabolites. There are three PPAR subtypes PPAR xcex1, PPAR xcex2 (also referred to as PPAR xcex4), and PPAR xcex3. Each receptor shows a different pattern of tissue expression, and differences in activation by structurally diverse compounds. PPAR xcex3, for instance, is expressed most abundantly in adipose tissue and at lower levels in skeletal muscle, heart, liver, intestine, kidney, vascular endothelial and smooth muscle cells as well as macrophages. PPAR receptors are associated with regulation of insulin sensitivity and blood glucose levels, macrophage differentiation, inflammatory response, and cell differentiation. Accordingly, PPARs have been associated with obesity, diabetes, carcinogenesis, hyperplasia, atherosclerosis, hyperlipidemia, and hypercholesterolemia.
In addition, PPARxcex1 agonists lower plasma triglycerides and LDL cholesterol and are therefore useful in treating hypertriglyceridemia, hyperlipidemia and obesity. PPAR xcex3 is associated with the development of non-insulin-dependent diabetes mellitus (NIDDM), hypertension, coronary artery disease, hyperlipidemia and certain malignancies. Finally, activation of PPAR xcex2 has been demonstrated to increase HDL levels. (Leibowitz, WO97/28149, August 1997.) More recently, a PPAR xcex2 selective agonist was reported to have shown a dose-related increase in serum HDL-C and decrease in LDL-C and VLDL-TG in insulin-resistant middle aged rhesus monkeys. (W. R. Oliver et al., PNAS, v. 98, pp. 5306-5311, 2001)
Antilipidemic and antidiabetic agents are still considered to have non-uniform effectiveness. The effectivieness of antidiabetic and antilipidemic therapies is limited, in part because of poor patient compliance due to unacceptable side effects. These side effects include diarrhea and gastrointestinal discomfort, and in the case of antidiabetics, edema, hypoglycemia and hepatoxicity. Furthermore, each type of drug does not work equally well in all patients.
For the reasons set forth above, there is a need for novel antilipidemic and antidiabetic agents that can be used alone or in combination. Furthermore, activation of PPARxcex2 alone or in combination with the simultaneous activation of PPAR xcex1 and/or PPAR xcex3 may be desirable in formulating a treatment for dyslipidemia.
The present invention provides compounds capable of altering PPAR activity. Compounds of the present invention are described by Formula I: 
or a pharmaceutically acceptable salt thereof, where:
T is a saturated or unsaturated, substituted or unsubstituted hydrocarbon chain or hydrocarbon-heteroatom chain having from 3 to 6 atoms wherein the carbon atom of position 2 is connected to the carbon atom of position 3 to form a five to eight member ring;
W is O, S, CH2, CR4R5, NR3, cycloalkylene, or heterocycloalkylene;
Y is absent, O, or CR4R5 where
Y is CR4R5 or absent when W is O, S, or NR3; and
Y is O or absent when W is CH2 or CR4R5;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, haloalkyl, xe2x80x94Oxe2x80x94(CH2)pCF3, halogen, nitro, cyano, xe2x80x94OH, xe2x80x94SH, xe2x80x94CF3, xe2x80x94S(O)palkyl, S(O)paryl, xe2x80x94(CH2)mOR3, xe2x80x94(CH2)mNR6R7, xe2x80x94COR3, xe2x80x94CO2H, xe2x80x94CO2R3, or xe2x80x94NR6R7;
R3 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
R4 and R5 are independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms;
R6 and R7 are independently hydrogen, alkyl, alkenyl, alkynyl, xe2x80x94COalkyl, xe2x80x94COaryl, cycloalkyl, xe2x80x94CO2alkyl, xe2x80x94CO2aryl, xe2x80x94SO2alkyl, xe2x80x94SO2aryl, or joined together to form a 4 to 7 member ring having 1 to 3 heteroatoms;
X0 and X1 are independently O or S;
Ar1 is substituted or unsubstituted aryl or heteroaryl;
m is 0 to 5;
n is 0 to 5; and
p is 0 to 2.
In one embodiment, the present invention provides compounds as described by Formula IIa, Formula IIb, Formula IIc, Formula IId, or Formula IIe: 
or a pharmaceutically acceptable salt thereof, where:
W is O, S, CH2, CR4R5, NR3, cycloalkylene, or heterocycloalkylene;
Y is absent, O, or CR4R5 where
Y is CR4R5 or absent when W is O, S, or NR3; and
Y is O or absent when W is CH2 or CR4R5;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, haloalkyl, xe2x80x94Oxe2x80x94(CH2)pCF3, halogen, nitro, cyano, xe2x80x94OH, xe2x80x94SH, xe2x80x94CF3, xe2x80x94S(O)palkyl, S(O)paryl, xe2x80x94(CH2)mOR3, xe2x80x94(CH2)mNR6R7, xe2x80x94COR3, xe2x80x94CO2H, xe2x80x94CO2R3, or xe2x80x94NR6R7;
R3 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
R4 and R5 are independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms;
R6 and R7 are independently hydrogen, alkyl, alkenyl, alkynyl, xe2x80x94COalkyl, xe2x80x94COaryl, cycloalkyl, xe2x80x94CO2alkyl, xe2x80x94CO2aryl, xe2x80x94SO2alkyl, xe2x80x94SO2aryl, or joined together to form a 4 to 7 member ring having 1 to 3 heteroatoms;
X0 and X1 are independently O or S;
Ar1 is substituted or unsubstituted aryl or heteroaryl;
m is 0 to 5;
n is 0 to 5;
p is 0 to 2; and
Y1, Y2, Y3 and Y4 are independently a carbon atom or a heteroatom wherein the carbon atom and the heteroatom are bonded to a sufficient number of hydrogen atoms or substituents to complete the valency of each atom with the proviso that Y1, Y2, Y3 and Y4 are not all heteroatoms and that not more than two adjacent atoms in Y1, Y2, Y3 and Y4 are heteroatoms and that in Formulae IIb, IIc, and IId, Y1, Y2, Y3 and Y4 are not all carbon.
In one embodiment, the present invention provides compounds as described by Formula IIIa or Formula IIIb: 
or a pharmaceutically acceptable salt thereof, where:
W is O, S, CH2, CR4R5, NR3, cycloalkylene, or heterocycloalkylene;
Y is absent, O, or CR4R5 where
Y is CR4R5 or absent when W is O, S, or NR3; and
Y is O or absent when W is CH2 or CR4R5;
R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, haloalkyl, xe2x80x94Oxe2x80x94(CH2)pCF3, halogen, nitro, cyano, xe2x80x94OH, xe2x80x94SH, xe2x80x94CF3, xe2x80x94S(O)palkyl, S(O)paryl, xe2x80x94(CH2)mOR3, xe2x80x94(CH2)mNR6R7, xe2x80x94COR3, xe2x80x94CO2H, xe2x80x94CO2R3, or xe2x80x94NR6R7;
R3 is hydrogen, alkyl, alkenyl, alkynyl, or aryl;
R4 and R5 are independently hydrogen, alkyl, alkenyl, alkynyl, or aryl, or joined together to form a 4 to 7 member ring having 0 to 3 heteroatoms;
R6 and R7 are independently hydrogen, alkyl, alkenyl, alkynyl, xe2x80x94COalkyl, xe2x80x94COaryl, cycloalkyl, xe2x80x94CO2alkyl, xe2x80x94CO2aryl, xe2x80x94SO2alkyl, xe2x80x94SO2aryl, or joined together to form a 4 to 7 member ring having 1 to 3 heteroatoms;
X0 and X1 are independently O or S;
Ar1 is substituted or unsubstituted aryl or heteroaryl;
m is 0 to 5;
n is 0 to 5;
p is 0 to 2; and
Z1, Z2, and Z3 are independently a carbon atom or a heteroatom wherein the carbon atom and the heteroatom are bonded to a sufficient number of hydrogen atoms or substituents to complete the valency of each atom with the proviso that Z1, Z2, and Z3 are not all heteroatoms and that in Formulae IIIa and IIIb Z1, Z2, and Z3 are not all carbon atoms.
In yet another embodiment of the present invention, a method of preparing the compounds of Formula I-III is provided. The method of the present invention includes reacting 
in a solvent in the presence of a base such as cesium carbonate, with 
where
T, R1, R2, R3, R4, R5, R6, R7, X0, X1, Ar1, m, n, and p are the same as described above;
X is a halogen; and
R10 is a lower alkyl.
In another embodiment of the present invention a pharmaceutical composition comprising a compound of Formula I and one or more pharmaceutically acceptable carriers, diluents, or excipients is provided.
In another embodiment of the present invention, a method of treating, preventing or controlling hypercholesteremia in a mammal is provided. The method comprises administering to the mammal in need thereof a therapeutically effective amount of the compounds of the present invention.
In another embodiment of the present invention a method for treating, preventing, or controlling obesity is provided.
In another embodiment of the present invention a method for treating, preventing, or controlling hyperglycemia is provided.
In another embodiment of the present invention a method for treating, preventing, or controlling atherosclerosis is provided.
In another embodiment of the present invention a method for treating, preventing, or controlling hypertriglyceridemia is provided.
In another embodiment of the present invention a method for treating, preventing, or controlling hyperinsulinemia is provided.
In another embodiment of the present invention a method for treating, preventing, or controlling diabetes is provided.
In another embodiment of the present invention a method for treating a patient exhibiting glucose disorders associated with circulating glucocorticoids, growth hormone, catecholamines, glucagon, or parathyroid hormone is provided.
For each disease state treatable, preventable, or controllable by the method of the present invention, a therapeutically effective amount of the compounds of the present invention are administered to the mammal in need thereof.
In yet another embodiment of the present invention, a method for preparing compounds of Formula I is provided.